- An Aldehyde Responsive, Cleavable Linker for Glucose Responsive Insulins
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A glucose responsive insulin (GRI) that responds to changes in blood glucose concentrations has remained an elusive goal. Here we describe the development of glucose cleavable linkers based on hydrazone and thiazolidine structures. We developed linkers with low levels of spontaneous hydrolysis but increased level of hydrolysis with rising concentrations of glucose, which demonstrated their glucose responsiveness in vitro. Lipidated hydrazones and thiazolidines were conjugated to the LysB29 side-chain of HI by pH-controlled acylations providing GRIs with glucose responsiveness confirmed in vitro for thiazolidines. Clamp studies showed increased glucose infusion at hyperglycemic conditions for one GRI indicative of a true glucose response. The glucose responsive cleavable linker in these GRIs allow changes in glucose levels to drive the release of active insulin from a circulating depot. We have demonstrated an unprecedented, chemically responsive linker concept for biopharmaceuticals.
- Mannerstedt, Karin,Mishra, Narendra Kumar,Engholm, Ebbe,Lundh, Morten,Madsen, Charlotte S.,Pedersen, Philip J.,Le-Huu, Priska,Pedersen, S?ren L.,Buch-M?nson, Nina,Borgstr?m, Bj?rn,Brimert, Thomas,Fink, Lisbeth N.,Fosgerau, Keld,Vrang, Niels,Jensen, Knud J.
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supporting information
p. 3166 - 3176
(2021/01/21)
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- Synthesis and pharmacological characterization of novel xanthine carboxylate amides as A2A adenosine receptor ligands exhibiting bronchospasmolytic activity
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The carboxylate amides of 8-phenyl-1,3-dimethylxanthine described herein represent a new series of selective ligands of the adenosine A2A receptors exhibiting bronchospasmolytic activity. The effects of location of 8-phenyl substitutions on the
- Yadav, Rakesh,Bansal, Ranju,Rohilla, Suman,Kachler, Sonja,Klotz, Karl-Norbert
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- 2-PHENYL-3H-IMIDAZO[4,5-B]PYRIDINE DERIVATES USEFUL AS INHIBITORS OF MAMMALIAN TYROSINE KINASE ROR1 ACTIVITY
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A compound of formula (I′) or (I′′) or a pharmaceutically acceptable salt thereof. The compound is an inhibitor of mammalian kinase enzyme activity, including ROR1 tyrosine kinase activity and may be used in the treatment of disorders associated with such activity.
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Page/Page column 103-104
(2016/09/22)
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- Discovery of histone deacetylase 8 selective inhibitors
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We have developed an efficient method for synthesizing candidate histone deacetylase (HDAC) inhibitors in 96-well plates, which are used directly in high-throughput screening. We selected building blocks having hydrazide, aldehyde and hydroxamic acid functionalities. The hydrazides were coupled with different aldehydes in DMSO. The resulting products have the previously identified 'cap/linker/biasing element' structure known to favor inhibition of HDACs. These compounds were assayed without further purification. HDAC8-selective inhibitors were discovered from this novel collection of compounds.
- Tang, Weiping,Luo, Tuoping,Greenberg, Edward F.,Bradner, James E.,Schreiber, Stuart L.
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supporting information; experimental part
p. 2601 - 2605
(2011/06/22)
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- Methods of treatment using an EP2 selective receptor agonist
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The present invention relates to methods of treating pulmonary hypertension, facilitating joint fusion, facilitating tendon and ligament repair, reducing the occurrence of secondary fracture, treating avascular necrosis, facilitating cartilage repair, facilitating bone healing after limb transplantation, facilitating liver regeneration, facilitating wound healing, reducing the occurrence of gastric ulceration, treating hypertension, facilitating the growth of tooth enamel or finger or toe nails, treating glaucoma, treating ocular hypertension, and repairing damage caused by metastatic bone disease using an EP2 selective receptor agonist.
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Page/Page column 46
(2010/02/13)
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- Prostaglandin agonists and their use to treat bone disorders
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This invention relates to prostaglandin agonists, methods of using such prostaglandin agonists, pharmaceutical compositions containing such prostaglandin agonists and kits containing such prostaglandin agonists. The prostaglandin agonists are useful for the treatment of bone disorders including osteoporosis.
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- Aryl carboxylic acid and aryl tetrazole derivatives as IP receptor modulators
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This invention relates to compounds which are generally IP receptor modulators, particularly IP receptor agonists, and which are represented by Formula I: wherein R1, R2, R3, R4, R5, A, and B are as defined in the specification, and individual isomers, racemic or non-racemic mixtures of isomers, and pharmaceutically acceptable salts or solvates thereof. The invention further relates to pharmaceutical compositions containing such compounds and methods for their use as therapeutic agents.
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- 3-AMIDINOANILINE DERIVATIVES, ACTIVATED BLOOD COAGULATION FACTOR X INHIBITORS, AND INTERMEDIATES FOR PRODUCING BOTH
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The present invention relates to a 3-amidinoaniline derivative represented by the general formula: wherein R represents a hydrogen atom, a lower alkyl group, a lower alkenyl group etc.; R1 represents a hydrogen atom, a hydroxy group, a lower alkyl group etc.; Y represents a single bond or an oxygen atom; and R2 represents a lower alkyl group or a group represented by the general formula: wherein n represents 1 or 2; and T represents a hydrogen atom or a group represented by the general formula:-C(=NH)-W wherein W represents a lower alkyl group; or a pharmaceutically acceptable salt thereof, which has a potent and selective activated blood coagulation factor X inhibitory activity, and an intermediate for producing both.
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- Porphyrin synthesis in surfactant solution: Multicomponent assembly in micelles
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A synthesis of meso-substituted porphyrins in anionic sodium dodecyl sulfate micelles has been developed. Polar, functionalized aromatic aldehydes condense reversibly with pyrrole in the micellar phase. Oxidation of the porphyrinogen then provides functionalized porphyrins in yields of 10-48%. Hydrophobic aldehydes condense irreversibly to give low yields at practical substrate concentrations. Synthesis in D2O solution results in per-β-deuterated porphyrins. A two-phase model is used to rationalize the dependence of porphyrin yield on reactant and surfactant concentration. Micelles are viewed as potential wells which promote porphyrinogen assembly by binding products more tightly than reactants.
- Bonar-Law, Richard P.
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p. 3623 - 3634
(2007/10/03)
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- Organopalladium Approaches to Prostaglandins. 6. Synthesis of Interphenylene Prostaglandin Endoperoxide Analogs Via Benzylpalladation of Bicyclic Alkenes.
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The reactions of norbornene, norbornadiene and 7-oxanorbornene with methyl 3-(chloromethyl)phenoxyacetate (4), optically pure (S)-1-octyn-3-ol (5), and 8percent Pd(PPh3)4 afford in one step satisfactory yields of the corresponding esters 6, 7 and 8 respectively, readily saponified to the first interphenylene prostaglandin endoperoxide analogs 10, 11 and 12 respectively.
- Larock, Richard C.,Babu, Srinivasan
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p. 2013 - 2020
(2007/10/02)
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- PGE1 -oxa phenylene compounds
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This invention is a group of PGE1 -type oxa-phenylene compounds, and processes for making them. These compounds are useful for a variety of pharmacological purposes, including anti-ulcer, inhibition of platelet aggregation, increase of nasal patency, labor inducement at term, and wound healing.
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- PGEo oxa-phenylene compounds
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This invention is a group of 13,14-dihydro-PGE1 -type (also referred to as PGEo -type) oxa-phenylene compounds, and processes for making them. These compounds are useful for a variety of pharmacological purposes, including anti-ulcer, inhibition of platelet aggregation, increase of nasal patency, labor inducement at term, and wound healing.
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- PGA1 -oxa-phenylene compounds
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This invention is a group of PGA1 -type oxa-phenylene compounds, and processes for making them. These compounds are useful for a variety of pharmacological purposes, including anti-ulcer, treatment of asthma, and management of renal dysfuction.
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- PGE2 -oxa-phenylene compounds
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This invention is a group of PGE2 -type oxa-phenylene compounds, and processes for making them. These compounds are useful for a variety of pharmacological purposes, including anti-ulcer, inhibition of platelet aggregation, increase of nasal patency, labor inducement at term, and wound healing.
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- Oxa-phenylene compounds
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This invention is a group of 17,18-didehydro-PG1 - and -PG2 -type oxa-phenylene compounds, and processes for making them. These compounds are useful for a variety of pharmacological purposes, including anti-ulcer, inhibition of platelet aggregation, increase of nasal patency, labor inducement at term, and wound healing.
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- PGF1β -oxa phenylene compounds
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This invention is a group of PGF1β -type and PGF2β -type oxa-phenylene compounds, and processes for making them. These compounds are useful for a variety of pharmacological purposes, including inhibition of platelet aggregation, treatment of asthma, labor inducement at term, and cervical dilation.
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- PGF1α -oxaphenylene compounds
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This invention is a group of PGF1α -type oxaphenylene compounds, and processes for making them. These compounds are useful for a variety of pharamcological purposes, including inhibition of platelet aggregation, treatment of asthma, labor inducement at term, and cervical dilation.
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